tbuckley/cabot-search huggingface dataset:
Abstract 3847: Tumor stem cell derived asymmetric dimethylarginine drives immune evasion via functional modulation of macrophages
Authors: Yiling Chen, AKaychia T. Lowery, Andres Becerril, Zaida T. Laventure, Shareda Ferguson, Kuan-Hui Ethan Chen
Journal: Cancer Research (2022)

Abstract Macrophages are the most abundant tumor infiltrating immune cells and perform diverse immune functions including phagocytosis and incitation of T cells to mount an immune attack against tumors. However, the macrophage plasticity can lead to different outcomes of tumor progression and the amino acid, arginine, plays a central role in macrophage dichotomy. The exact role of arginine on the management of macrophage polarization is not completely understood. We have discovered that a methylated arginine metabolite, asymmetric dimethylarginine (ADMA), serves as an important regulator of macrophage functions. Upon stimulation by ADMA, macrophages have reduced survival and show a delayed tumor-phagocytic capacity. Additionally, ADMA blocks the Nitric Oxide Synthase (NOS) but not the Arginase activity in macrophages leading to a tendency of M2-like phenotype polarization. ADMA has minor effect on tumor cell proliferation but significantly drives the epithelial to mesenchymal transition. Tumor cells, particularly the tumor stem cells, are the major sources of ADMA. Production and secretion of ADMA by tumor (stem) cells profoundly increase when co-cultured with activated T cells or treated with T cell associated inflammatory cytokine, interferon-gamma (IFN-r). IFN-r initiates autophagy of tumor (stem) cells and inhibition of autophagy reduces the output of ADMA by tumor (stem) cells. Similarly, IFN-r enhances the proteasomal degradation and inhibition of the proteasomal pathway also reduces the ADMA production induced by IFN-r. In summary, our work shows that tumor (stem) cells may escape from immune surveillance (such as their exposure to activated T lymphocytes or to cytotoxic cytokine, IFN-r) through the secretion of ADMA generated via both autophagic and proteasomal pathways. Citation Format: Yiling Chen, AKaychia T. Lowery, Andres Becerril, Zaida T. Laventure, Shareda Ferguson, Kuan-Hui Ethan Chen. Tumor stem cell derived asymmetric dimethylarginine drives immune evasion via functional modulation of macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3847.
Abstract 6247: Evaluation of AS-10, identified based on SAR studies of newly generated organoselenium compounds, as a potential colorectal cancer therapeutic acting potentially by acetylating histones
Authors: Hannah Johnson, Amandeep Singh, Asif Raza, Deepkamal Karelia, Daniel Plano, Shantu Amin, Arun Sharma
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) is the third most common form of cancer diagnosed in the United States. Standard treatment for CRC utilizes a combination therapy composed of 5-fluorouracil, oxaliplatin, and folinic acid, known as FOLFOX. It has been established that patients with CRC tend to develop drug resistance to FOLFOX leading to a need for new chemotherapeutic treatments. Recent work has established that AS-10, a small molecule established for its promising role in treating pancreatic cancer, to be capable of inhibiting the growth of a range of CRC cell lines, including FOLFOX resistant CRC cells. Twenty-four cyclic and open chain analogs of AS-10 were synthesized and evaluated for their activity in inhibiting the viability of different cancer cells in vitro. The cell viability of these compounds was compared to AS-10 in the cell lines of pancreatic carcinoma (MiaPaCa2), lung carcinoma (H460), colorectal adenocarcinoma (HT29), colorectal carcinoma (HCT116), and FOLFOX resistant HT29 and HCT116 cells. Based on the IC50 values observed from these initial studies, only ASA-7, an open-chain alkyl selenocyanate, could treat all cancer cell lines in a similar concentration range of AS-10. Dose-response curves completed in 6 CRC cell lines indicated IC50 values in the range of 1-2 µM for AS-10 and 3.3-6.6µM for ASA-7. Cell viability evaluation in normal kidney (HEK293T) and colon (FHC) cell lines indicated AS-10 to be less toxic as compared to ASA-7. A similar trend was observed in vivo - AS-10 was 4 times more tolerable in mice as compared to ASA-7. A HCT116 xenograft study demonstrated the ability of AS-10 to significantly inhibit tumor growth in vivo without any apparent systemic toxicity. Moreover, AS-10 was assessed for its ability to act as an acetyl donor for histone acetyltransferase (HAT) and was found to initiate HAT activity in the absence of Acetyl-CoA in pancreatic epithelioid carcinoma (Panc-1) and colorectal carcinoma (HCT116) cells. In conclusion, AS-10 was identified as the best among the 24 analogs, in vitro and in vivo, when treating CRC and found to be capable of inducing HAT activity in both pancreatic and colorectal carcinoma elucidating a possible mechanism of action. Citation Format: Hannah Johnson, Amandeep Singh, Asif Raza, Deepkamal Karelia, Daniel Plano, Shantu Amin, Arun Sharma. Evaluation of AS-10, identified based on SAR studies of newly generated organoselenium compounds, as a potential colorectal cancer therapeutic acting potentially by acetylating histones [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6247.
Abstract 94: PRMT5 substrate recruitment as a therapeutic target in CDKN2A/MTAP null cancers
Authors: Kathleen M. Mulvaney, Brian McMillan, Christa Blomquist, Nischal Acharya, Matthew Ranaghan, Devishi Kesar, Alessandra Ianari, William Sellers
Journal: Cancer Research (2022)

Abstract PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP-null cancers. PRMT5 uses adaptor proteins for substrate recruitment through a previously undefined mechanism. Here, we identify an evolutionarily conserved peptide sequence shared among the three known substrate adaptors (CLNS1A, RIOK1, and COPR5) and show that it is necessary and sufficient for interaction with PRMT5. We demonstrate that PRMT5 uses modular adaptor proteins containing a common binding motif for substrate recruitment, comparable with other enzyme classes such as kinases and E3 ligases. We structurally resolve the interface with PRMT5 and show via genetic perturbation that it is required for methylation of adaptor-recruited substrates including the spliceosome, histones, and ribosomal complexes. Furthermore, disruption of this site affects Sm spliceosome activity, leading to intron retention. Genetic disruption of the PRMT5-substrate adaptor interface impairs growth of MTAP-null tumor cells and is thus a site for development of therapeutic inhibitors of PRMT5. Current efforts are focused on understanding whether PRMT5-substrate adaptor disruption synergizes with immune therapies or new classes of PRMT5 inhibitors in CDKN2A/MTAP null cancer. Citation Format: Kathleen M. Mulvaney, Brian McMillan, Christa Blomquist, Nischal Acharya, Matthew Ranaghan, Devishi Kesar, Alessandra Ianari, William Sellers. PRMT5 substrate recruitment as a therapeutic target in CDKN2A/MTAP null cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 94.
Abstract 1745: Exploiting vulnerabilities to nanoparticle induced lipid peroxidation and proteotoxicity to treat drug resistant lung cancer
Authors: Christina Snyder, Monica Rohde, Ravi N. Singh
Journal: Cancer Research (2022)

Abstract Protein quality control plays an essential role in cell survival. Clinically translated strategies to target protein quality control in cancer show some efficacy, but off-target effects are severe. We are investigating a new approach using nanomaterials to induce lipid peroxidation to trigger a cascade of protein oxidation, protein misfolding, and decreased protein degradative capacity in cancer cells without affecting normal cells. Our studies show that silver nanoparticles (AgNPs) cause dramatic increases in lipid peroxidation, 4-hydroxynonenal adducts (4-HNE), protein oxidation, protein aggregation, and proteotoxic stress signaling in a mesenchymal-like subset of non-small cell lung (NSCLC) and other cancers at doses that do not affect normal cells in vitro or vivo. Notably, AgNP sensitive NSCLCs are inherently resistant to clinically relevant therapies including epidermal growth factor receptor tyrosine kinase inhibitors ((EGFR-TKIs) e.g. erlotinib, gefitinib, olfatinib) and cisplatin. We identified two defining characteristics causing some cancers to be sensitive to AgNPs. The first is enrichment of cell membranes in polyunsaturated fatty acids (PUFAs), especially arachidonic (AA) and adrenic acid (AdA), which are prone to oxidation. The second is high-level synthesis and secretion of extracellular matrix (ECM), especially fibronectin and collagen, which places AgNP sensitive cancers under substantial baseline endoplasmic reticulum stress, making them susceptible to agents that increase proteotoxicity. Mechanistically, we find that in PUFA-enriched cancers, signaling from ECM sustains the AgNP sensitive phenotype by stimulating Akt activity and stabilizing cytoplasmic β-catenin. Transcriptionally active β-catenin increases expression of fibronectin and collagen, resulting in a positive feedback loop locking cells into the AgNP sensitive phenotype. Use of AgNPs to targeting vulnerabilities associated with ECM synthesis and signaling downstream of β-catenin is a novel approach to overcoming multiple EGFR-TKI resistance mechanisms. Ultimately, our goal is to elucidate the precise mechanism by which AgNPs overcome resistance to clinically available EGFR-TKIs. Identification of the specific drivers of sensitivity to AgNPs (and potentially other metal nanoparticles) will guide development of therapeutic metal nanoparticles, enable selection of cancer patients who will benefit most or are at greatest risk to nanomaterial exposure, and will spur innovation of other treatments that exploit the vulnerabilities we identify. Citation Format: Christina Snyder, Monica Rohde, Ravi N. Singh. Exploiting vulnerabilities to nanoparticle induced lipid peroxidation and proteotoxicity to treat drug resistant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1745.
Abstract 5833: Functional characterization of TP53 mutations in human fallopian tube secretory epithelial cells
Authors: Ya-Yun Cheng, Denise Prosser, Liudmila Velikokhatnaya, Anna Lokshin
Journal: Cancer Research (2022)

Abstract Ovarian cancer is the fifth leading cause of cancer-related death in women and mainly develops in older women. High-grade serous carcinoma (HGSC) is the most common and deadly subtype of ovarian cancer and recently has been shown to arise from the distal end of the fallopian tube. About 96% of HGSC cases were found to contain mutations in TP53 and missense mutation was the most frequent type. It is known that TP53 mutation is an early event occurred in HGSC and may drive tumorigenesis. Different TP53 mutations have been reported to promote cell survival, metastatic potential or tumorigenicity. However, the roles of TP53 mutations and the underlying molecular mechanisms have not been satisfactorily understood in HGSC. In order to functionally characterize TP53 mutations in a systematic approach, primary human fallopian tube secretory epithelial cells (FTSECs) from normal fallopian tube specimens were used. We isolated and transduced FTSECs with hTERT for extending cell lifespan. Afterwards, both overexpression and knock down experiments were performed. According to the IARC TP53 Database, we selected four TP53 hotspot mutations found in ovarian cancer patients for further investigation. The mutant TP53, including R175H, Y220C, R273C, and R273H, were expressed in FTSECs. Meanwhile, knock down was achieved by introducing shRNAs targeting TP53. The transduced cells were subjected to RNA sequencing experiments to identify the significantly influenced genes and signaling pathways. The candidate genes and pathways will be validated in FTSECs and a panel of ovarian cancer cell lines. Functional assays, such as cell viability assay, migration/invasion assay, and metabolism assay, will be performed to study the effects of TP53 mutations. The results can provide further understanding of TP53 mutations and the downstream signaling in HGSC tumorigenesis. Citation Format: Ya-Yun Cheng, Denise Prosser, Liudmila Velikokhatnaya, Anna Lokshin. Functional characterization of TP53 mutations in human fallopian tube secretory epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5833.
Abstract 647: Association between adrenal-restrictive HSD3B1 inheritance and hormone independent subtypes of endometrial and breast cancer
Authors: Jeffrey M. McManus, Roberto Vargas, Peter Bazeley, Navin Sabharwal, Nima Sharifi
Journal: Cancer Research (2022)

Abstract Breast and endometrial cancer are both malignancies that can be classified into subtypes based on their hormone dependence, such as estrogen receptor (ER)-positive vs. ER-negative breast cancer and low-grade vs. high-grade endometrial cancer. The gene HSD3B1 encodes the steroid metabolism enzyme 3β-hydroxysteroid dehydrogenase 1, which catalyzes a critical step in conversion of adrenal precursor steroids to potent androgens and estrogens. Associations between the missense-encoding germline variant rs1047303 in HSD3B1 have been described to affect outcomes of castration-resistant prostate cancer and associated with ER positivity in postmenopausal breast cancer. The adrenal-permissive 1245C allele enables greater production of androgens and estrogens from adrenal precursors, whereas the adrenal-restrictive 1245A allele limits this reaction pathway. Using data from The Cancer Genome Atlas’s TCGA-UCEC and TCGA-BRCA projects, we interrogated whether the adrenal-restrictive rs1047303 genotype was associated with less hormone-driven genomic clusters of endometrial and breast cancer. We determined the genotype frequencies for different tumor subtypes, as classified by the genomic analysis of Sanchez-Vega, et al. (2018). The adrenal-restrictive HSD3B1(1245A) allele was associated with the copy number (CN) high cluster of endometrial cancer (OR 1.59, 95% CI 1.12-2.26, p = 0.0098), notably composed of serous and high-grade endometrioid endometrial cancers which are less estrogen-dependent than low-grade endometrioid tumors. Similarly, the adrenal-restrictive HSD3B1(1245A) was associated with the basal subtype of breast cancer (OR 1.54 [1.13-2.09], p = 0.0057), a subtype that is largely ER-negative and is known to share genomic features with serous-type endometrial cancers. Lastly, we interrogated overall survival of endometrial cancer patients in the UK Biobank and found that patients homozygous for the adrenal-restrictive HSD3B1(1245A) had worse overall survival (HR 1.39 [1.16-1.68], p = 0.00049) and cancer-specific survival (HR 1.39 [1.14-1.70], p = 0.0013), a finding consistent with the A allele being enriched in the more aggressive CN-high subtype of endometrial cancer. Taken together, these findings suggest a role for adrenal-restrictive vs. adrenal-permissive steroidogenesis, by way of rs1047303 genotype, in the development of and/or outcomes from at least three different commonly hormone-associated types of cancer: prostate, breast, and endometrial. Citation Format: Jeffrey M. McManus, Roberto Vargas, Peter Bazeley, Navin Sabharwal, Nima Sharifi. Association between adrenal-restrictive HSD3B1 inheritance and hormone independent subtypes of endometrial and breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 647.
Abstract 6158: Rewiring cancer associated fibroblasts using nanomedicines improves immunotherapy efficacy
Authors: Ahmed Elzoghby, May Freag, Mostafa Mohammed, Krishna Maremanda, Hae Lin Jang, Shiladitya Sengupta
Journal: Cancer Research (2022)

Abstract The failure of large number of patients to respond to cancer immunotherapy remains a formidable challenge. The immunosuppressive tumor microenvironment (TME) can hinder the capability of cytotoxic T cells to fight cancer. In this regard, cancer associated fibroblasts (CAFs) are among the most abundant stromal cells in TME responsible for immunosuppression. Therefore, reversal of the immunosuppressive phenotype of CAFs and is a major therapeutic goal. Cancer cells secrete exosomes and other factors to reprogram fibroblasts and induce their differentiation into pro-tumorigenic CAFs. Also, cancer cells maintain the activated fibroblast phenotype via triggering major signaling pathways e.g., TGFβ1, FGFR, or β-catenin pathways in the fibroblasts. Here, our goal was to maintain a normalized quiescent phenotype of fibroblasts to enhance the efficacy of immune checkpoint blockade. We demonstrated that a tumor-targeted EpCAM antibody modified shikonin/GW4869 combination liposomes synergistically reduces the biogenesis and release of exosomes from A549 lung cancer cells which significantly inhibits differentiation of MRC5 lung fibroblasts into CAFs. In parallel, we showed the efficacy of TAS-120/ICG-001 FGFR-Wnt/β-catenin inhibitor combination liposomes decorated with GPR77 and CD10 targeting antibodies to switch the acquired activated CAFs phenotype to a quiescent one. Co-administration of both liposomes in low drug doses significantly enhanced the infiltration of cytotoxic CD8+ T cells and improved the antitumor efficacy of αPD-L1 antibody in LLC syngeneic mice model of lung cancer. In conclusion, simultaneous blockage of the tumoral exosome-mediated activation of fibroblasts and FGFR-Wnt/β-catenin signaling may constitute an outstanding immunotherapeutic modality. Citation Format: Ahmed Elzoghby, May Freag, Mostafa Mohammed, Krishna Maremanda, Hae Lin Jang, Shiladitya Sengupta. Rewiring cancer associated fibroblasts using nanomedicines improves immunotherapy efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6158.
Abstract 1288: STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition in BRCA-associated breast cancer
Authors: Heta Jadhav, Constantia Pantelidou, Aditi Kothari, Renyan Liu, Gerburg Wulf, Jennifer L. Guerriero, Geoffrey I. Shapiro
Journal: Cancer Research (2022)

Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors exert their efficacy by inducing synthetic lethal effects, as well as cGAS/STING-mediated immune responses in BRCA- and other homologous recombination repair-deficient cancer cells. Here, we investigated whether the immunologic and therapeutic effects of PARP inhibition in BRCA-deficient breast cancer models could be augmented by synthetic cyclic dinucleotide agonists of STING. In in vitro experiments, combined olaparib-mediated PARP inhibition and ADU-S100-mediated STING agonism induced a greater degree of STING pathway activation and proinflammatory cytokine production compared to monotherapies in BRCA1-deficient human MDA-MB-436 cells and mouse triple-negative breast cancer cell lines derived from a genetically engineered model of BRCA-deficient breast cancer. In vivo experiments were conducted in mice bearing completely established tumors derived from the genetically engineered mouse model expanded syngeneically. In this model, the combination also induced an improved immune response compared to either monotherapy alone, evidenced by a greater degree of cytotoxic T cell recruitment and activation, and enhanced dendritic cell activation and antigen presentation. Nanostring mRNA analysis indicated that combinatorial effects were the result of augmented interferon signaling and antigen processing, as well as heightened leukocyte and dendritic cell functions. The combination markedly improved anti-tumor efficacy in vivo compared to monotherapy treatment, with evidence of complete tumor clearance and prolongation of survival. Finally, in mice treated with the combination, tumors could not be re-established upon rechallenge, indicating the induction of immunologic memory. These results support the development of combined PARP inhibition and STING agonism in BRCA-associated breast cancer. Citation Format: Heta Jadhav, Constantia Pantelidou, Aditi Kothari, Renyan Liu, Gerburg Wulf, Jennifer L. Guerriero, Geoffrey I. Shapiro. STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition in BRCA-associated breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1288.
Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders
Authors: Gregory Hook, Thomas Reinheckel, Junjun Ni, Zhou Wu, Mark Kindy, Christoph Peters, Vivian Hook
Journal: Pharmacological Reviews (2022)

Cathepsin B (CTSB) is a powerful lysosomal protease. This review evaluated <i>CTSB</i> gene knockout (KO) outcomes for amelioration of brain dysfunctions in neurologic diseases and aging animal models. Deletion of the <i>CTSB</i> gene resulted in significant improvements in behavioral deficits, neuropathology, and/or biomarkers in traumatic brain injury, ischemia, inflammatory pain, opiate tolerance, epilepsy, aging, transgenic Alzheimer's disease (AD), and periodontitis AD models as shown in 12 studies. One study found beneficial effects for double <i>CTSB</i> and cathepsin S KO mice in a multiple sclerosis model. Transgenic AD models using amyloid precursor protein (APP) mimicking common sporadic AD in three studies showed that <i>CTSB</i> KO improved memory, neuropathology, and biomarkers; two studies used APP representing rare familial AD and found no <i>CTSB</i> KO effect, and two studies used highly engineered APP constructs and reported slight increases in a biomarker. In clinical studies, all reports found that CTSB enzyme was upregulated in diverse neurologic disorders, including AD in which elevated CTSB was positively correlated with cognitive dysfunction. In a wide range of neurologic animal models, CTSB was also upregulated and not downregulated. Further, human genetic mutation data provided precedence for CTSB upregulation causing disease. Thus, the consilience of data is that <i>CTSB</i> gene KO results in improved brain dysfunction and reduced pathology through blockade of CTSB enzyme upregulation that causes human neurologic disease phenotypes. The overall findings provide strong support for CTSB as a rational drug target and for CTSB inhibitors as therapeutic candidates for a wide range of neurologic disorders. <h3>Significance Statement</h3> This review provides a comprehensive compilation of the extensive data on the effects of deleting the cathepsin B (<i>CTSB</i>) gene in neurological and aging mouse models of brain disorders. Mice lacking the <i>CTSB</i> gene display improved neurobehavioral deficits, reduced neuropathology, and amelioration of neuronal cell death and inflammatory biomarkers. The significance of the compelling CTSB evidence is that the data consilience validates CTSB as a drug target for discovery of CTSB inhibitors as potential therapeutics for treating numerous neurological diseases.